A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis Renata Belfort, M.D., Stephen A. Harrison, M.D., Kenneth Brown, M.D., Celia Darland, R.D., Joan Finch, R.N., Jean Hardies, Ph.D., Bogdan Balas, M.D., Amalia Gastaldelli, Ph.D., Fermin Tio, M.D., Joseph Pulcini, M.D., Rachele Berria, M.D., Jennie Z. Ma, Ph.D., Sunil Dwivedi, M.D., Russell Havranek, M.D., Chris Fincke, M.D., Ralph DeFronzo, M.D., George A. Bannayan, M.D., Steven Schenker, M.D., and Kenneth Cusi, M.D N EnglJ Med 2006;355: Prof 김병호 /R 2 조용덕

Predominantly lobular necroinflammation Insulin resistance With or without centrilobular fibrosis The accumulation of hepatic fat Nonalcoholic steatohepatitis 21 Introduction

ursodeoxycholic acid vitamin E lipid-lowering agents orlistat pentoxifilline Multiple pharmacologic interventions Have been attempted with variable success Trials of glucose-lowering agents such as metformin and Thiazolidinedione have yielded promising results 31 Weight loss remains the standard of care because no pharmacologic therapy has conclusively proved to be effective for the treatment of this condition

Nonalcoholic steatohepatitis activation of the intracellular proinflammatory signaling pathways low plasma adiponectin Insulin resistance Pioglitazone, a thiazolidinedione derivative, is a peroxisome proliferator–activated receptor (PPAR ) agonist that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes Thiazolidinediones reverse insulin resistance by ameliorating insulin resistance in adipose tissues, the liver, and muscles. Thiazolidinediones increase plasma adiponectin levels, activate AMP-activated protein kinase,stimulate fatty acid oxidation, inhibit hepatic fatty acid synthesis thiazolidinediones have antiinflammatory effects.

This study conducted a randomized, double-blind, placebo-controlled trial to determine whether pioglitazone plus a calorie-restricted diet as compared with placebo plus a calorie-restricted diet may reverse the metabolic and histologic abnormalities in patients with nonalcoholic steatohepatitis.

Methods 55 patients with impaired glucose tolerance or type 2 diabetes hypocaloric diet (500Kcal/day) plus pioglitazone (45 mg daily) hypocaloric diet (500Kcal/day) plus placebo Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test liver biopsy–confirmed nonalcoholic steatohepatitis

RESULTS

54% 40% 58%

RESULTS 48%

RESULTS

Conclusons In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone